The following is a summary of “p.Cys1281Tyr variant in the hinge module/flap region of thyroglobulin causes intracellular transport disorder and congenital hypothyroidism,” published in the July 2023 issue of Molecular and Cellular Endocrinology by Pio et al.

Depending on the severity of the defect, congenital hypothyroidism (CH) caused by thyroglobulin (TG) variants results in deficient serum TG levels with normal or enlarged thyroid glands and autosomal recessive inheritance. This study aimed to functionally characterize the p.Cys1281Tyr variant of the TG gene to expand our understanding of the molecular mechanisms underlying CH. 

To discover evidence supporting the hypothesis that the p.Cys1281Tyr variant affects TG folding, amino acid prediction, 3D modeling, and transient expression analysis in HEK293T cells were performed. About 18 of the 21 “in silico” algorithms predict that the p.Cys1281Tyr variant will have a negative influence. The full-length 3D model of p.Cys1281Tyr TG demonstrated disulfide bond disruption between the cysteines at positions 1,249 and 1,281 and a rearrangement of the TG structure.

In contrast, transient expression analysis revealed that p.Cys1281Tyr causes the protein to be retained within the cell. Consequently, these results demonstrate that this pathogenic variant prevents TG from performing its function in the biosynthesis of thyroid hormones, resulting in CH. In conclusion, our findings corroborate the pathophysiological significance of TG misfolding due to the p.Cys1281Tyr variant in the hinge module/flap region of TG.

Source: sciencedirect.com/science/article/abs/pii/S0303720723000990